Hepatic fibrosis, defined by excessive accumulation of extracellular matrix (ECM) and resultant loss of pliability and liver function, is the result of wound-healing responses triggered by either acute or chronic liver injury (Bataller and Brenner, 2005; Hernandez-Gea and Friedman, 2011; Lee and Friedman, 2011). The main causes of liver injury leading to fibrosis in industrialized countries include chronic hepatitis virus (HBV/HCV) infection, alcohol abuse, and increasingly, nonalcoholic steatohepatitis (NASH) (Friedman, 1999, 2003; Friedman and Bansal, 2006; Siegmund et al., 2005). With persistent injury, there is progressive deposition of fibrillar collagens, eventually leading to parenchymal nodules surrounded by collagen bands, the histological signature of hepatic cirrhosis (Bataller and Brenner, 2005; Friedman, 2003).
Chronic liver disease and cirrhosis represents a major global health concern (Bataller and Brenner, 2005). In Australia and the UK, chronic liver disease is the 5th most common cause of death, after heart disease, cancer, stroke and chest disease (Williams, 2006). In the US, they are ranked as the 8th most common cause of mortality (Kim et al., 2002). Currently, no anti-fibrotic therapies for chronic liver disease have been approved by the FDA (Cohen-Naftaly and Friedman, 2011), and where the underlying cause of the liver disease cannot be ameliorated, therapeutic options are limited to addressing the consequent complications, such as portal hypertension, hepatocellular carcinoma and liver failure. Therefore, a greater understanding of molecular mechanisms regulating the hepatic fibrogenic response in liver is needed for identification of novel targets for successful anti-fibrotic therapies.
The central players in liver fibrosis are non-parenchymal cells (NPCs) such as hepatic stellate cells (HSCs) (Bataller and Brenner, 2005; Bouwens et al., 1992), which are the main producers of ECM (Friedman, 2008; Friedman et al., 1985; Reynaert et al., 2002). In the healthy liver, HSCs are retinoid (Vitamin A) storage cells located in the space of Disse, between the sinusoidal endothelium and hepatocytes (Friedman, 2008). Following injury, paracrine stimuli cause HSCs to undergo dramatic phenotypic changes (in a process called activation), whereby they exhibit proliferation, contractility and loss of retinoid stores, accompanied by secretion of chemokines, cytokines and pathological extracellular matrix components (Friedman, 2008; Geerts, 2001). While the precise mechanisms regulating this process have yet to be elucidated, transforming growth factor β1 (TGFβ1) signaling is recognized as one of the most potent pro-fibrotic pathways responsible for ECM synthesis (Breitkopf et al., 2006; Inagaki and Okazaki, 2007).
TGFβ is a multifunctional cytokine with profound effects on cell division, differentiation, migration, adhesion, organization and death. There are three major isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3) and TGFβ1 is the principal isoform implicated in liver fibrosis (Inagaki and Okazaki, 2007). Following liver injury, TGFβ1, derived from both paracrine and autocrine sources, binds to type I and type II serine/threonine receptor kinases on the cell surface of HSCs (Inagaki and Okazaki, 2007). Subsequently, its downstream effectors SMAD2 and SMAD3 are phosphorylated and released into the cytosol, where they form a complex with SMAD4. This SMAD complex can then translocate into the nucleus, recognize SMAD-binding elements (SBE) on the genome and directly regulate target genes (Feng and Derynck, 2005; Massague et al., 2005). Thus, deciphering the TGFβ-SMAD transcriptional network in HSCs and understanding how it can be controlled by extracellular and intracellular factors is key to development of effective anti-fibrotic strategies.